The long term objectives of the present proposal are to gain knowledge about the reaction of the central catecholamine systems to pathologic conditions. Specifically, with two models of genetically determined neuronal losses, seen in the Purkinje cell degeneration mutant mouse and the weaver mutant mouse, we will be able to investigate a) the effects on a major catecholamine system when one of its target neuronal populations (the Purkinje cell) degenerates; b) the effects on a major target field (caudo-putamen) when its major and important catecholamine neuronal input (substantia nigra, cells of pars compacta) degenerate. In the Purkinje cell degeneration mutant the Purkinje cells degenerate at the end of cerebellar maturation, but norepinephrine levels in the cerebellum are not reduced. Therefore, we will monitor the plastic changes of the catecholaminergic axons and determine whether the catecholamine turnover is altered by the loss of the postsynaptic neuron. In the weaver mutant a marked deficiency of the dopamine system is present and is due to depletion of dopaminergic neurons in the substantia nigra. We will analyze the effects of the atrophy of the substantia nigra on the postsynaptic neurons of the caudate nucleus. These models will provide insight into afferent and efferent relationships which catecholamine neurons are able to maintain under conditions of degeneration of either their target neurons or cells of the catecholamine nucleus itself. The comprehension of the biology of the systems of the catecholaminergic neurons and their modality of reaction in pathologic conditions is of relevance to neurology, psychiatry and medicine; in fact the importance of the central catecholamine system in the expression of a number of behaviors, as substrates for the mediation for the action of a variety of drugs, and a possible substrate for diseases such as Parkinsonism, schizophrenia and depressive illnesses are well recognized. The proposed goals will be achieved by bringing together numerous techniques including neurohistochemical, electron microscopic, Golgi impregnation techniques, and computerized cytomorphometry that will be correlated with sophisticated neurochemical and neuropharmacological techniques.